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STUDY QUESTION Do women with polycystic ovary syndrome (PCOS) have a greater risk of adverse pregnancy complications (gestational diabetes, preeclampsia, cesarean section, placental abnormalities) and neonatal outcomes (preterm birth, small for gestational age, prolonged delivery hospitalization) compared to women without a PCOS diagnosis and does this risk vary by BMI, subfertility and fertility treatment utilization? SUMMARY ANSWER Deliveries to women with a history of PCOS were at greater risk of complications associated with cardiometabolic function, including gestational diabetes and preeclampsia, as well as preterm birth and prolonged length of delivery hospitalization. WHAT IS KNOWN ALREADY Prior research has suggested that women with PCOS may be at increased risk of adverse pregnancy outcomes. However, findings have been inconsistent possibly due to lack of consistent adjustment for confounding factors, small samples size and other sources of bias. STUDY DESIGN, SIZE, DURATION Massachusetts deliveries among women ≥18 years old during 2013–2017 from state vital records linked to hospital discharges, observational stays and emergency department visits were linked to the Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS) and the Massachusetts All-Payers Claims Database (APCD). PARTICIPANTS/MATERIALS, SETTING, METHODS PCOS was identified by ICD9 and ICD10 codes in APCD prior to index delivery. Relative risks (RRs) and 95% CI for pregnancy and delivery complications were modeled using generalized estimating equations with a log link and a Poisson distribution to take multiple cycles into account and were adjusted a priori for maternal age, BMI, race/ethnicity, education, plurality, birth year, chronic hypertension and chronic diabetes. Tests for homogeneity investigated differences between maternal pre-pregnancy BMI categories ( MAIN RESULTS AND THE ROLE OF CHANCE Among 91 825 deliveries, 3.9% had a history of PCOS. Women with a history of PCOS had a 51% greater risk of gestational diabetes (CI: 1.38–1.65) and a 25% greater risk of preeclampsia (CI: 1.15–1.35) compared to women without a diagnosis of PCOS. Neonates born to women with a history of PCOS were more likely to be born preterm (RR: 1.17, CI: 1.06–1.29) and more likely to have a prolonged delivery hospitalization after additionally adjusting for gestational age (RR: 1.23, CI: 1.09–1.40) compared to those of women without a diagnosis of PCOS. The risk for gestational diabetes for women with PCOS was greater among women with a pre-pregnancy BMI LIMITATIONS, REASONS FOR CAUTION PCOS was defined by ICD documentation prior to delivery so there may be women with undiagnosed PCOS or PCOS diagnosed after delivery included in the unexposed group. The study population is limited to deliveries within Massachusetts among most private insurance payers and inpatient or observational hospitalization in Massachusetts during the follow-up window, therefore there may be diagnoses and or deliveries outside of the state or outside of our sample that were not captured. WIDER IMPLICATIONS OF THE FINDINGS In this population-based study, women with a history of PCOS were at greater risk of pregnancy complications associated with cardiometabolic function and preterm birth. Obstetricians should be aware of patients’ PCOS status and closely monitor for potential pregnancy complications to improve maternal and infant perinatal health outcomes. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by the NIH (R01HD067270). S.A.M. receives grant funding from NIH, AbbVie and the Marriot Family Foundation; payment/honoraria from the University of British Columbia, World Endometriosis Research Foundation and Huilun Shanghai; travel support for attending meetings for ESHRE 2019, IASP 2019, National Endometriosis Network UK meeting 2019; SRI 2022, ESHRE 2022; participates on the data safety monitoring board/advisory board for AbbVie, Roche, Frontiers in Reproductive Health; and has a leadership role in the Society for Women’s Health Research, World Endometriosis Research Foundation, World Endometriosis Society, American Society for Reproductive Medicine and ESHRE. The other authors have no conflicts of interest. TRIAL REGISTRATION NUMBER N/A.

Summary Background Polycystic ovary syndrome (PCOS) is a multifactorial hormonal disorder accompanied by impairment of endometrial function and structure. Pomegranate is recognized for its role in normalizing the female sex hormones in PCOS with little known about its effect on the accompanying endometrial histological alterations. Aim of the work To assess the possible ameliorative role of pomegranate juice extract (PJE) on endometrial injury in a rat model of PCOS. Material and methods Forty adult albino rats were equally divided into 4 groups; control, PJE-treated (400 mg/kg/day for 3 weeks), letrozole-treated (PCOS) (1 mg/kg/day for 3 weeks), and PJE & PCOS groups. Serum Follicle-stimulating hormone (FSH), Luteinizing hormone (LH), testosterone, estradiol, and tissue malondialdehyde (MDA) were assayed. Uterine samples were processed for histological staining with hematoxylin & eosin and Masson's trichrome stains, Ki67 and androgen receptor immunohistochemical staining, and scanning electron microscopy. Results PCOS group revealed a significant increase in serum FSH, LH, testosterone, estradiol, and tissue MDA. Uterine sections depicted various histological alterations in the endometrium with signs of inflammation. A significant increase in the endometrial collagen fiber content, as well as a significant upregulation in Ki67 and androgen receptor immunohistochemical expression were detected. Scanning electron microscopy showed a significant decrease in the mean number of pinopodes. Concomitant administration of PJE efficiently restored the studied biochemical, histological, and immunohistochemical parameters. Conclusion PJE ameliorated PCOS accompanying endometrial histological alterations through its antioxidant, anti-inflammatory, anti-fibrotic, anti-proliferative, and anti-androgenic effects most probably due to its polyphenols content.

Background and objectives Weight loss is the mainstay of management for women with polycystic ovarian syndrome (PCOS). However, lifestyle and dietary modifications, and gastric banding have generally poor long-term efficacy. We aimed to investigate whether gastric bypass is equally efficacious in women with or without PCOS. Methods We performed a matched case–control study of primary Roux-en-Y gastric bypass surgery in women with PCOS (cases, n = 30) compared to women without PCOS (controls, n = 60) matched for baseline age, body mass index (BMI) and presence or absence of type 2 diabetes (T2D). Data shown represent mean values. Results At 24 months after surgery the 90 participants (age 36.1 years) experienced significant reductions in BMI (53.4 vs. 34.9 kg/m2, p Conclusion In women with PCOS with morbid obesity, gastric bypass resulted in significant weight loss and metabolic outcomes similar to women without PCOS.

Study Objective The purpose of this study was to examine feasibility, acceptability, and preliminary efficacy of a mindfulness-based healthy lifestyle self-management intervention with adolescents and young adults diagnosed with polycystic ovary syndrome (PCOS). Design A pilot randomized controlled trial using a pre-post design was used. Setting Central Texas. Participants: Individuals aged 14-23 with a diagnosis of PCOS. Interventions The PCOS Kind Mind Program integrates a manualized mindfulness training program (Taming the Adolescent Mind) with health education in four key areas of self-management and health promotion; (1) medication adherence, (2) nutrition, (3) physical activity, and (4) sleep. Main Outcome Measures Psychological distress, mindfulness, physical activity strategies, nutrition and exercise self-efficacy. Results Linear regression models revealed that those in the PCOS Kind Mind condition reported significantly higher nutrition self-efficacy (β = 6.50, 95% CI = 1.71 – 11.28, p = 0.013, d = 0.48), physical activity strategies (β = 0.41, 95% CI = 0.04 – 0.79, p = 0.040, d = 0.67), and physical activity self-efficacy (β = 0.48, 95% CI = 0.07 – 0.88, p = 0.028, d = 0.46). Conclusion The PCOS Kind Mind Program improved self-efficacy in the key areas of nutrition and physical activity and increased physical activity strategies in adolescents and young people with PCOS. These findings are encouraging and suggest the need for larger scale, randomized controlled trials with longer-term follow-up in order to more robustly evaluate the PCOS Kind Mind Program on the psychological and physiological health of adolescents and young people with PCOS.

Background The existing data regarding the impact of Polycystic Ovary Syndrome (PCOS) on the risk of developing cardiovascular disease (CVD) are conflicting. Aim To explore the effect of PCOS status on the occurrence of silent coronary artery disease (CAD)/CVD. Methods A total of 1591 women without CVD at baseline, aged 18–45 years, including 356 PCOS patients (defined by the Rotterdam criteria) and 1235 eumenorrheic non-hirsute women without polycystic ovarian morphology (controls), were selected from the Tehran Lipid and Glucose Study (TLGS). The median follow-up was 15.4 years, and most participants were in their late reproductive years at the end of the study. Silent CAD and CVD outcomes in PCOS and control groups were compared according to the multivariable-adjusted hazard ratios (HRs) and cumulative hazard functions. Results There was no difference in CVD risk factors between the PCOS and control groups. After controlling for confounders, PCOS status did not increase the risk of silent CAD (HR: 0.96, 95% CI 0.86–1.08). Regardless of PCOS status, women with a history of silent CAD showed 2.25 times higher CVD events than those without this history (95% CI 1.63–3.10). PCOS status reduced the CVD incidence by 42%, independently of silent CAD or traditional risk factors (HR: 0.58, 95% CI 0.35–0.98). Conclusions Whereas silent CAD, regardless of PCOS, accelerated CVD, PCOS preserved it, most likely due to a combination of protective factors, including the endocrine pattern in the late reproductive period, environmental/social elements, and recruiting additional counseling and lifestyle modifications.

Funder: European Foundation for the Study of Diabetes (EFSD)/Sanofi; Id: http://dx.doi.org/10.13039/501100001648, Objective: Polycystic ovary syndrome (PCOS) has been associated with an increased risk of coronary artery disease (CAD). However, it remains uncertain whether this increased risk is the result of PCOS per se or, alternatively, is explained by obesity, a common feature of PCOS. The aim of this study was to assess the causal association between PCOS and CAD and the role of obesity herein. Design and Methods: We conducted two‐sample Mendelian randomisation analyses in large‐scale, female‐specific datasets to study the association between genetically predicted (1) risk of PCOS and risk of CAD, (2) body mass index (BMI) and risk of PCOS and (3) BMI and risk of CAD. Primary analyses were conducted with the inverse‐variance weighted (IVW) method. Simple median, penalized weighted median and contamination mixture analyses were performed to assess the robustness of the outcomes. Results: IVW analyses did not show a statistically significant association between PCOS and CAD (odds ratio [OR]: 0.99, 95% confidence interval [CI]: 0.89, 1.11). In contrast, genetically predicted BMI was statistically significantly associated with an increased odds of PCOS (OR: 3.21, 95% CI: 2.26, 4.56) and CAD (OR: 1.38, 95% CI: 1.14, 1.67). Similar results were obtained when secondary analyses were performed. Conclusion: These sex‐specific analyses show that the genetically predicted risk of PCOS is not associated with the risk of CAD. Instead, the genetically predicted risk of obesity (and its downstream metabolic effects) is the common denominator of both PCOS and CAD risk.

Research question Do cumulative live birth rates (CLBR) differ between polycystic ovary syndrome (PCOS) phenotypes when a freeze-all strategy is used to prevent ovarian hyperstimulation syndrome (OHSS) after ovarian stimulation (OS)? Design This is a single-centre, retrospective cohort study including 422 women with PCOS as defined by Rotterdam criteria or with PCO-like ovarian morphology-only (PCOM) in whom, between January 2015 and December 2019, a freeze-all strategy was applied after GnRH agonist triggering in the context of hyper-response defined as ≥18 follicles of ≥11 mm in their first or second IVF/ICSI cycle in a tertiary referral hospital. The primary outcome was CLBR resulting from the transfer of all cryopreserved embryos from the same IVF/ICSI cycle. Analysis was performed by multivariate logistic regression analysis adjusting for confounders. Results In total, 91/422 (21.6%) patients had PCOS phenotype A (hyperandrogenism + ovulation disorder + PCOM = HOP), 33/422 (7.8%) had phenotype C (hyperandrogenism + PCOM = HP), 161/422 (38.2%) had phenotype D (ovulation disorder + PCOM = OP) and 137/422 (32.5%) had PCOM. Unadjusted CLBR was similar among the groups (69.2%, 69.7%, 79.5% and 67.9%, respectively; p= 0.11). The multivariate logistic regression model adjusting for age, BMI, number of oocytes, fertilization rate and embryo stage at vitrification confirmed that the PCOS/PCOM phenotype did not have any impact on CLBR [OR 0.72, CI 0.24-2.14 (phenotype C); OR 1.55, CI 0.71-3.36 (phenotype D); OR 0.84, CI 0.39-1.83 (PCOM); p= 0.2, with phenotype A as reference]. Conclusions In subfertile women with PCOS eligible for ART, hyper-response after OS confers excellent cumulative live birth rates of ∼70%, irrespective of the phenotype, when a freeze-all strategy is used. This contrasts with the unfavourable clinical outcomes that have previously been observed in hyperandrogenic PCOS women who underwent mild OS targeting normal ovarian response and fresh embryo transfer. The data should however be interpreted with caution as the retrospective nature of the study holds the possibility of unmeasured confounding factors. The results cannot be generalized to all ART cycles in women with polycystic ovaries as they pertain to those cycles in which hyper-response is observed after OS.

Background: Polycystic ovary syndrome (PCOS) is the most common endocrine abnormality among women of reproductive age. Insulin resistance is known as the hallmark of PCOS that leads to hyperinsulinemia and type 2 diabetes in PCOS patients. Objective: This study aimed to evaluate the expression pattern of IRS1 as a candidate gene in insulin resistance development in the PCOS rat models. Methods: In this study, estradiol valerate was used for PCOS induction. Then, all of the rats were divided into five experimental groups and treated with Astragalus hamosus extract. Ethanol was used for extraction by Soxhlet, and extracts were analyzed by GC-MS. Ovarian morphology was analyzed using histological experiments. Finally, the expression of IRS1 and hormonal titration of testosterone and insulin were evaluated using qRT-PCR and ELISA assays, respectively. Results: Induction of PCOS led to an increase in body weight, which decreased after treatment with the extract. Histological assessment declared an increased number of corpora lutea in treated groups and reduced cystic follicles compared to the PCOS group. Astragalus hamosus extract-treated groups exhibited decreased levels of insulin and testosterone compared to the PCOS group. qRT-PCR results showed an increase in the expression levels of IRS1 in the treated groups compared to the PCOS group. Conclusions: This study indicated the impact of Astragalus hamosus extract on PCOS by clarifying the increased levels of IRS1 expression in the treated groups compared to the PCOS group.

Background There is evidence of a relationship between prenatal excess androgen exposure and central nervous developmental problems and attention-deficit/hyperactivity disorder (ADHD) in the offspring of mothers with polycystic ovary syndrome (PCOS). Purpose Here we aimed to use a meta-analysis to investigate whether the offspring of mothers with PCOS are at an increased chance of developing ADHD. Methods Three main English databases were searched for articles published through December 2020. The Newcastle-Ottawa Scale (NOS) was used to assess study quality. Study heterogeneity was determined using I2 statistics and publication bias was assessed using Begg's and Egger's tests. The results are presented as odds ratio (OR) and relative ratio (RR) estimates with 95% confidence intervals (CI) using a random-effects model. Results Six articles (three cohort and three case-control studies; 401,413 total ADHD cases) met the study criteria. Maternal PCOS was associated with an increased risk of ADHD in the offspring based on OR and RR (OR, 1.42; 95% CI, 1.27-1.57) and (RR, 1.43; 95% CI, 1.35-1.51), respectively. There was no heterogeneity among the included articles based on OR (I2 = 0.0%, P = 0.588) and RR (I2 = 0.0%, P = 0.878). Conclusion Our study showed that maternal PCOS is a risk factor for ADHD. Therefore, screening their offspring for ADHD should be considered part of the comprehensive clinical care of women with PCOS.

Research Question To evaluate whether endometrial scratch improved the chance of a live birth in women with PCOS undergoing ovulation induction and trying to conceive. Design An international, multicentre, randomised, sham-controlled trial across six fertility clinics in three countries (New Zealand, United Kingdom and Brazil). Women with a diagnosis of PCOS who were planning to commence ovulation induction cycles (at least three cycles) in order to conceive were randomly assigned to receive the pipelle (scratch) procedure or a sham (placebo) procedure in the first cycle of ovulation induction. Women kept a diary of ovulation induction and sexual intercourse timing over three consecutive cycles and pregnancies were followed-up to live birth. Primary outcome was live birth and secondary outcomes were clinical pregnancy, ongoing pregnancy, multiple pregnancy, adverse pregnancy outcomes, neonatal outcomes, bleeding following procedure and pain score following procedure. Results 117 women were randomised; 58 to the scratch group and 59 to the sham group. Live birth occurred in 11 (19%) women in the scratch group and 14 (24%) in the sham group (OR 0.76, 95% confidence interval of 0.30 to 1.92). Secondary outcomes were similar in each group. Significantly higher pain scores were reported in the scratch group (adjusted mean difference 3.2, 95% confidence interval of 2.5 to 3.9) when measured on a visual-analogue scale. Conclusion We did not detect a difference in live birth rate for women with PCOS who received an endometrial scratch when trying to conceive using ovulation induction, however, uncertainty remains due to the small sample size in our study.

Research Question To investigate which characteristics of patients with a thin endometrium (endometrial thickness [EMT] ≤7.5 mm on human chorionic gonadotrophin [HCG] trigger day) suggest the possibility of an EMT >7.5 mm in the subsequent frozen cycle, and to build a prediction nomogram. Design Data were collected from the university-affiliated Center for Reproductive Medicine between January 2013 and September 2019. Multivariable logistic regression was used to generate the final prediction model and construct the nomogram. Model performances were quantified by discrimination and calibration. Results The predictive variables that entered the final model were: hysteroscopic adhesiolysis history, polycystic ovary syndrome status, application of clomiphene in the ovarian stimulation process, the ovarian stimulation protocol, and the endometrial preparation protocol. The receiver operating characteristic curve for the final model and validation cohort was 0.76 (95% confidence interval [CI]: 0.722–0.797) and 0.71 (95% CI: 0.664–0.759), respectively. Discrimination performed well in both the modelling and validation cohorts. Conclusions We conclude that in women with a thin endometrium (EMT ≤7.5 mm on HCG trigger day), the absence of a hysteroscopic adhesiolysis history, the presence of polycystic ovary syndrome, the application of clomiphene in the ovarian stimulation process, the application of a GnRH agonist short protocol, mild stimulation protocol, natural cycle protocol, and natural cycle for endometrial preparation are prognostic for an increased possibility of an EMT >7.5 mm in the subsequent frozen cycle.

Numerous evidence implies complex interrelations between polycystic ovary syndrome (PCOS) and hypertension (HT) in reproductive-age women. In this study, we aimed to investigate the potential strain differences in ovarian morphology, hemodynamic, and biochemical characteristics in an androgen-induced PCOS rat model. A total of 24 rats of 3 weeks old (12 Wistar Kyoto – WK and 12 spontaneously hypertensive rats – SHR) were divided into four groups: WK, WK PCOS, SHR, and SHR PCOS. PCOS was induced by daily s.c. injections of testosterone enanthate (1 mg/100 g body weight) administered for 5 weeks. PCOS induction led to estrus cyclicity cessation, cystic ovarian appearance, and sex hormones disturbances in both strains. The morphometric parameters in ovaries were altered in a manner of PCOS-related changes in both strains (higher number in preantral, atretic, and cystic follicles). Ultrasonographically, a significant decrease in ovarian volume (OV) was registered in PCOS groups but also in SHR compared to WK rats. All blood pressure parameters were higher in SHR compared to WK. PCOS modeling increased systolic, mean arterial, and pulse pressure in WK strain, while in SHR, only mean arterial and pulse pressure were higher. Alterations in oxidative stress parameters could provide a molecular basis for PCOS-related changes: in PCOS groups, thiobarbituric acid reactive substance and superoxide anion radical levels were higher in both strains, while superoxide dismutase and glutathione were significantly lowered.

Bariatric surgery is an effective treatment for severe obesity. Several studies have been conducted on the effects of bariatric surgery on the reproductive function of women with obesity who do not have polycystic ovary syndrome (PCOS).To evaluate the effects of bariatric surgery on the menstruation and reproductive related hormones of women of childbearing age with who do not have PCOS.A systematic review and meta-analysis at a university hospital.Online databases were searched for all studies reporting the efficacy of bariatric surgery for women with obesity until March 2021. The language of publication was limited to English and Chinese. Incidence of abnormal menstruation and reproductive-related hormone levels were the primary outcomes.Fifteen studies comprising 725 patients were enrolled in this meta-analysis. Results showed a significantly lower incidence of abnormal menstruation (relative risk: .40, 95% confidence interval [CI]: .20-.79, P = .008) after bariatric surgery. Moreover, bariatric surgery led to a decrease in serum insulin levels (mean difference [MD] = -13.12 mIU/L, 95% CI: -15.03 to -11.22, P .00001), glucose (MD = -.91 mmol/L, 95% CI: -1.26 to -.56, P.00001), triglyceride (MD = -.61 g/L, 95% CI: -.76 to -.46, P.00001), total testosterone (MD = -.22 ng/mL, 95% CI: -.24 to -.20, P.00001), dehydroepiandrosterone (DHEA) (MD = -25.34 μg/dL, 95% CI: -31.19 to -19.49, P.00001), estradiol (MD = -25.13 pg/mL, 95% CI: -34.13 to -16.13, P.00001), and anti-Mullerian hormone (AMH) (MD = -.40 ng/mL, 95% CI: -.67 to -.13, P = .003). Serum sex hormone binding globulin (SHBG) levels increased after bariatric surgery (MD = 43.99 nmol/L, 95% CI: 34.99-52.99, P.00001).Bariatric surgery can lower fasting insulin, glucose, and triglyceride levels, reduce the incidence of abnormal menstruation, decrease total serum testosterone, DHEA, estradiol, and AMH levels, and increase SHBG level for women with obesity of childbearing age who do not have PCOS. This meta-analysis indicated that bariatric surgery could be effective in improving reproductive function for women with severe obesity.

Context Women with polycystic ovary syndrome (PCOS) have an increased risk of metabolic syndrome (MetS). Both PCOS and MetS are associated with excess weight. Objective To examine the effect of a three-component lifestyle intervention (LSI) with or without short message service (SMS+ or SMS−, respectively) on the prevalence and severity of MetS and metabolic parameters, compared to care as usual (CAU). Design Randomized controlled trial. Methods Women diagnosed with PCOS and a BMI >25 kg/m2 (n = 183) were either assigned to a 1-year three-component (cognitive behavioural therapy, diet, and exercise) LSI, with or without SMS support, or to CAU which provided weight-loss advice only. Main outcome measures included changes in the prevalence of MetS, the continuous MetS severity z-score (cMetS z-score), metabolic parameters, and the impact of weight loss. Results After 1 year, the decrease in the cMetS z-score was greater in the SMS+ group than the CAU group (−0.39, P = 0.015). The prevalence of MetS changed with −21.6% (P = 0.037), −16.5% (P = 0.190), and +7.0% (P = 0.509) in both LSI groups and CAU group, respectively. A post hoc analysis for both LSI groups combined vs CAU resulted in a MetS difference of −25.9% (P = 0.046). Moreover, weight loss per se resulted in significantly favourable effects on all metabolic parameters. Conclusions This three-component LSI was more successful in improving metabolic health compared to CAU. Therefore, we recommend this intervention to women with PCOS and excess weight, provided that a clinically relevant weight loss is being pursued.

Research question Do women with polycystic ovary syndrome (PCOS) have a different fat intake pattern to women without PCOS? Design Case–control study of 276 women between 20 and 35 years old from the Murcia region of Spain. Cases (n = 121) attended the Department of Gynaecology and Obstetrics of the University Clinical Hospital and were diagnosed with PCOS using Rotterdam criteria. Controls (n = 155) were women without PCOS attending the gynaecological outpatient clinic for routine gynaecological examinations. Data from clinical, gynaecological and analytical examinations were collected, including a food frequency questionnaire. Associations between fat intake and presence of PCOS and its phenotypes were examined using multiple logistic regression, adjusting for potential confounding factors. Results Although no association was found between fatty acid intake and PCOS, significant associations were observed for some PCOS phenotypes. The PCOS phenotype characterized by hyperandrogenism + oligo/amenorrhoea + polycystic ovarian morphology (‘H+O+POM’) was significantly associated with a higher intake of polyunsaturated fat (odds ratio [OR] 4.0; 95% confidence interval [CI] 1.1–14.2; fourth quartile of highest intake [Q4] versus lowest intake quartile as reference [Q1]) and omega-6 fatty acids (OR 3.5; 95% CI 1.01–12.4; Q3 versus Q1). The ‘H+O’ phenotype was positively associated with saturated fat intake (OR 6.9; 95% CI 1.1–41.6; Q4 versus Q1). Conclusion This exploratory study suggests that higher intakes of specific fatty acids are related to some PCOS phenotypes although no association was found for PCOS on a global basis. It is recommended that studies with larger sample size be performed to further explore these associations, thus contributing to establishing recommendations about fat intake adapted to different PCOS phenotypes.

Objective: In this study we aimed to assess anorexigenic peptide levels in patients with or without polycystic ovary syndrome (PCOS) and their effects on assisted reproductive treatment (ART) outcomes. Methods: A prospective case-control study was conducted in a tertiary care university-based ART clinic. Eighty-three patients were included in the study. The PCOS group included 41 patients, and the non-PCOS group included 42 controls. The 2003 Rotterdam criteria were used for PCOS patient selection. The ART indications in the non-PCOS group were tubal factor or unexplained infertility. Venous blood samples were taken on the third day of the menstrual cycle to determine the serum anorexigenic peptide levels. The enzyme-linked immunosorbent assay method was used for laboratory analyses. Results: In the PCOS group, serum obestatin levels were significantly lower than in the control group, but serum anorexigenic peptide levels were similar in PCOS patients with or without clinical pregnancy. Ovarian hyperstimulation syndrome (OHSS) was diagnosed only in PCOS patients, and the obestatin levels of OHSS patients were significantly lower than those of other PCOS patients. Conclusions: Baseline anorexigenic peptide levels did not affect the clinical pregnancy rate in ART cycles. Obestatin may play a role in the pathophysiology of OHSS; this possibility should be confirmed in further research.

Studies investigating the relationship between sex hormones, inflammatory mediators and joint disorders have reported that sex hormones affect the pathogenesis of joint disorders. We aimed to investigate temporomandibular joint disorder (TJD) in polycystic ovary syndrome (PCOS) and the possible role of systemic mediators and sex hormones in TJD pathogenesis.PCOS patients (n = 45) and controls (n = 30) aged 20-40 years, were enrolled in this case-control study. TJD diagnosis was performed by the specialist and blood samples were tested in the early follicular phase and on the 21 st (midluteal) day to investigate the levels of estrogen, progesterone, matrix metalloproteinase (MMP) 1-8-9, interleukin (IL)-1ß and Tumor necrosis factor (TNF)-α.TJD incidence was significantly higher in PCOS than the control group (51.1% and 6.9% respectively, p 0.01). Midluteal progesterone (p 0.01) was lower in PCOS group than the controls (p 0.01). TNF-α (p 0.01), MMP 1 (p 0.01) and MMP 8 (p = 0.02) levels were found significantly higher in PCOS than the control group. Further, Progesterone levels were found significantly lower in TJD (+) PCOS patients than TJD (-) PCOS patients. However, significant difference was not found between the PCOS TJD (+) and PCOS TJD (-) patients for estrogen, MMP 1, MMP 8, MMP 9, TNF-α and IL-1ß.TJD frequency was found significantly increased in PCOS patients. Related with this, TJD co-occurrence should be kept in mind in the diagnosing and treatment process of PCOS due to hormonal alteration.

Objective: We aimed to evaluate associations between the ratio of serum estrone (E1) to estradiol (E2) and parameters related to serum glucose metabolism and insulin resistance in women with polycystic ovary syndrome (PCOS). Methods: In total, 133 women between the ages of 18 and 33 diagnosed with PCOS were enrolled in this study. All participants with PCOS underwent blood tests to determine hormonal and biochemical metabolic parameters and a standard 2-hour 75-g oral glucose tolerance test. They were divided into two groups according to the serum E1-to-E2 ratio: group 1 (E1/E2 ratio

Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease globally and is estimated to affect approximately 25% of the world's population. Data about the prevalence and incidence of NAFLD in Africa are scarce, but the prevalence is estimated to be 13·5% for the general population. This is likely to be an underestimate considering the increasing burden of non-communicable diseases, particularly the rising prevalence of obesity and type 2 diabetes, driven by the overlapping challenges of food insecurity, nutritional transition, and associated increased consumption of calorie-dense foods. Establishing the true prevalence of NAFLD, raising public awareness around the risk factors behind the increase in NAFLD, and proactively addressing all components of metabolic syndrome will be important to combat this silent epidemic, which will have long-term health-care costs and economic consequences for the region.

Polycystic ovarian syndrome (PCOS) is the main cause of infertility in women. It is frequently associated with reduced progesterone production by human luteinised granulosa cells (hlGCs). However, the molecular mechanisms involved in these steroidogenesis alterations in PCOS patients are unclear. In a dihydrotestosterone-induced PCOS mouse model, steroid production is maintained in the setting of chemokine-like receptor 1 (Cmklr1) knockout. Thus, chemerin and chemerin receptors in terms of expression and progesterone regulation could be different in control and PCOS hlGCs. We first confirmed that progesterone levels in both plasma (P < 0.0001) and follicular fluid (FF) (P < 0.0001) were significantly reduced in PCOS normal weight women compared to control women. These data were associated with a lower STAR mRNA expression in both in vivo (P < 0.0001) and in vitro (P < 0.0001) hlGCs from PCOS women. Secondly, chemerin FF levels (P < 0.0001) and RARRES2 (P < 0.05) and CMKLR1 (P < 0.0001) mRNA levels in GCs were higher in PCOS normal weight patients. Thirdly, treatment of hlGCs with a specific nanobody (the VHH CA4910) targeting the human receptor for CMKLR1 leading to its inactivation abolished chemerin-induced progesterone inhibition, suggesting the involvement of CMKLR1 in this process. Furthermore, the inhibition of progesterone secretion induced by chemerin was two-fold higher in PCOS hlGCs (P < 0.05). Moreover, the VHH CA4910 reinstated a normal progesterone secretion with lower concentrations in PCOS hlGCs, suggesting a different chemerin sensitivity between PCOS and control hlGCs. Thus, chemerin, through CMKLR1, could be involved in the steroidogenesis alterations in PCOS hlGCs.

Summary Background Polycystic ovary syndrome (PCOS) is a common endocrine disorder among reproductive-age women, and is associated with cardiovascular diseases as well as non-alcoholic fatty liver disease. The recent evidence suggested the beneficial effects of l -carnitine in women with PCOS. Objective The present study aimed to investigate the effect of l -carnitine supplementation on liver fat content and cardiometabolic outcomes in overweight/obese women with PCOS. Methods The present study was designed as a 12-week double-blind, randomized controlled clinical trial. Sixty-two overweight/obese women with PCOS were assigned into the treatment (received 1000 mg/d l -carnitine capsule) and the control (received placebo capsule) groups. The outcomes included lipid accumulation product (LAP), atherogenic index of plasma (AIP), atherogenic coefficient (AC) and Castelli II indices. Results At the end of the trial, there was no significant difference between the treatment and the control groups in terms of LAP (−1.1 vs. −4.0; P = 0.45), AIP (0.0 vs. −0.09; P = 0.14), AC (−0.2 vs. −0.8; P = 0.06) and Castelli II index (−0.2 vs. −0.6; P = 0.07) after controlling the mean change of waist circumference. Conclusion l -carnitine supplementation for 12 weeks has no beneficial effect on liver fat content and cardiometabolic outcomes in overweight or obese women with PCOS. Trial registration: Registered on 30 December 2019 at Iranian Registry of Clinical Trials IRCT20191016045131N1.

Polycystic ovary syndrome (PCOS) is a common endocrinopathy in women of reproductive age. Although its essential clinical manifestation includes a plethora of symptoms and signs, which largely reflects the underlying hyperandrogenism, oligo/anovulation, and polycystic ovarian morphology, PCOS may also be associated with many metabolic derangements. These metabolic derangements happen to overlap with many of the core constituents of the metabolic syndrome (MBS)—increased insulin resistance, central obesity, and dyslipidemia. The two disorders also display similarly increased risks for certain metabolic and vascular diseases, such as type 2 diabetes mellitus, hypertension, and cardiovascular diseases. Due to the many similarities between metabolic syndrome and PCOS, this review aims to examine the evidence concerning the overlapping features, the risks for comorbidities, possible shared mechanisms, and treatment strategies in patients with coexisting PCOS and MBS.

To determine the relationships between circulating sex hormone-binding globulin (SHBG) and oxidized low-density lipoprotein (ox-LDL), total oxidant status, total antioxidant capacity, oxidative stress index, malondialdehyde, and the high-density lipoprotein (HDL) inflammatory index in patients with polycystic ovary syndrome (PCOS) and to investigate the effect of oxidative stress on the expression of SHBG and its mechanism in HepG2 cells.Cross-sectional study.University hospital.A total of 533 women with PCOS and 292 control women were included.None.Circulating SHBG, hormones, and metabolic and oxidative stress indices were determined in all subjects. The effects of ox-LDL and ox-HDL on the mRNA and protein expression of SHBG and related transcription factors were observed in HepG2 cells.The HDL inflammatory index, total oxidant status, oxidative stress index, and malondialdehyde levels were significantly higher in the three PCOS subgroups with different SHBG levels than in the controls. The ox-LDL and total antioxidant capacity were higher in the PCOS subgroups with SHBG levels75th percentile compared with the controls or the PCOS subgroup with SHBG levels ≥75th percentile. In HepG2 cells, the SHBG concentration in the culture supernatant, the mRNA levels of SHBG and hepatocyte nuclear factor-4α (HNF-4α), and the protein levels of HNF-4α were significantly lower in ox-LDL- and ox-HDL-treated cells than in the control cells and lipoprotein-treated cells.Oxidative stress inhibits the expression and secretion of SHBG by downregulating HNF-4α in vitro and may be an important factor promoting the occurrence of hyperandrogenemia in PCOS.

Introduction: Polycystic Ovary Syndrome (PCOS) is the most common endocrine disorder in women of reproductive age. PCOS is a heterogeneous complex disorder of defined aetiology. Some studies report its association with various endocrine, metabolic and immunological abnormalities. The hunger hormones ghrelin and leptin affect the pathogenesis of PCOS and might lead to the development of Metabolic Syndrome (MS) in obese women. Aim: The study aims at evaluating the role of ghrelin and leptin level in females with polycystic ovary syndrome as a biochemical marker for the diagnosis and monitoring progression. Subjects and Methods: The study included one hundred PCOS patients and fifty apparently healthy subjects with regular menstrual cycle, visiting gynecology outpatient clinic of Kalar General Hospital, from the beginning of February 2015 to the end of June 2015. Body Mass Index (BMI) along with serum ghrelin, leptin, Luteinizing Hormone (LH), Follicle Stimulating Hormone (FSH) and testosterone levels were measured for both groups. Serum leptin was determined using sandwich ELISA, while serum ghrelin was determined using competitive ELISA. Differences between patient and control groups were assessed by using a t-test. Also, one-way Anova was used to test the relationships among different groups. Results: A significant decrease in ghrelin level and an increase in leptin levels in women with PCOS were observed compared to the control group. Also, a significant elevation in serum levels of LH, Testosterone, Prolactin, and a decrease in serum FSH in PCOS patients were observed, when compared to the control group. Additionally, serum ghrelin decreased and serum leptin level increased significantly in women with PCOS compared to controls in all age and BMI groups. Conclusion: A significant decrease in ghrelin and an increase in leptin in PCOS patients were observed than in controls, indicating that they are at high risk for metabolic syndrome development.

Objective The molecular mechanism that triggers polycystic ovary syndrome (PCOS) is mysterious. Abnormal development of ovarian granulosa cells(GCs) is one of the causes of PCOSMethods The study was carried out by using RNA-seq to detect the different gene expression levels in ovarian GCs between 3 patients with PCOS and 4 normal controls. To further verify the above results, GCs from 22 patients with PCOS and 21 controls with normal ovulation were collected to perform the RT-PCR analysisResults The results found Hedgehog signaling pathway(Hh) members, Ihh and Ptch2 were abnormally highly expressed in the PT. The qPCR results also indicated that the expression levels of other Hh signaling pathway downstream members, Ptch1, Gli1, and Gli2 in the PCOS group (PT) were significantly higher than those in the control group (NT). Besides, the expression of TNF-α mRNA in PCOS patients was higher than that in the control group. Finally, the Hh signaling pathway inhibitor, cyclopamine, can decrease the apoptosis of PCOS ovarian granulosa cellsConclusions These results suggest that abnormally activated Hh signaling pathway, especially Ihh signal, may have a profound influence on PCOS.

Background: Polycystic ovary syndrome (PCOS) is a common reproductive and metabolic disorder characterized by high androgen levels. The aim of this study was to evaluate the effects of hyperandrogenism on the hypothalamus and subsequently on the food intake and obesity in females. Methods: A dihydroxy testosterone (DHT)-induced rat model was established to recapitulate the hyperandrogenism features of PCOS patients. Body weight and food intake of the rats were recorded. The food intake of DHT-induced rats was restricted by pair feeding to exclude possible effects of weight gain on the hypothalamus. The expression levels of relevant proteins and mRNAs in the hypothalamus and primary hypothalamic neurons exposed to DHT were analyzed by Western blotting and RT-PCR, respectively. The leptin levels in the serum and cerebrospinal fluid (CSF) were measured, and leptin was injected via the intracerebroventricular (ICV) route to test the leptin sensitivity of the hypothalamus. Results: The excessive prepuberty androgen levels in the DHT-induced rats markedly elevated food intake prior to weight gain. Consistent with this, the expression of neuropeptide Y and agouti-related peptide mRNAs was upregulated, which occurred prior to obesity and even with restricted food intake. In addition, the hypothalamic sensitivity to insulin and leptin was also impaired in the DHT-induced rats before obesity and with restricted food intake. DHT significantly reduced the leptin levels in the CSF, and ICV injection of leptin inhibited the DHT-induced increase in food intake. Conclusions: Androgen excess increased food intake in rats and promoted obesity by downregulating insulin and leptin signaling in the hypothalamus, most likely by suppressing leptin levels in the CSF.

STUDY QUESTION Does in vitro maturation (IVM) result in non-inferior cumulative live birth rates compared to those after standard in vitro fertilization (IVF) in infertile women with polycystic ovary syndrome (PCOS)? SUMMARY ANSWER One cycle of IVM, without any stimulation, was inferior to one cycle of standard IVF in women with PCOS in terms of 6-month cumulative live birth rates, when choosing single vitrified-warmed blastocyst transfer. WHAT IS KNOWN ALREADY IVM is an emerging alternative treatment for women with PCOS who need assisted reproductive technology. Since a minimal or even zero dose of gonadotropins are required in the IVM procedure, the occurrence of ovarian hyperstimulation syndrome (OHSS) is eliminated. Only one clinical trial comparing the pregnancy outcome between IVM with FSH priming and IVF has been reported. However, it is still unknown whether IVM treatment without any stimulation can offer a similar live birth outcome in women with PCOS as compared to that in women receiving the standard IVF procedure with ovarian stimulation. STUDY DESIGN, SIZE, DURATION This single-centre, open-label randomized controlled non-inferiority trial in an academic infertility centre in China was performed between March 2018 and July 2019. PARTICIPANTS/MATERIALS, SETTING, METHODS Women aged 20–38 years with PCOS and infertility scheduled for their first IVF attempt were eligible. In total, 351 women were randomly allocated to receive one cycle of unstimulated IVM (n = 175) or one cycle of standard IVF with a flexible GnRH antagonist protocol and hCG as ovulatory trigger (n = 176). A freeze-all and single blastocyst transfer strategy was used in both groups. The primary outcome was ongoing pregnancy (leading to live birth) within 6 months after randomization. A non-inferiority margin of 15% was considered. MAIN RESULTS AND THE ROLE OF CHANCE The IVM procedure without additional gonadotropin resulted in a lower ongoing pregnancy (leading to live birth) within 6 months after randomization compared to standard IVF treatment (22.3% vs. 50.6%; rate difference −28.3%; 95% confidence interval [CI]: −37.9% to −18.7%). Moderate-severe OHSS did not occur in the IVM group, while in the IVF group, ten women (5.7%) had moderate OHSS and one woman (0.6%) had severe OHSS. There was no statistically significant difference in the occurrence of obstetric and perinatal complications. LIMITATIONS, REASONS FOR CAUTION The trial was conducted using an IVM protocol without additional stimulation in a single centre, which may limit its generalizability. In addition, a GnRH agonist trigger rather than hCG for IVF stimulation in women with PCOS would be more consistent with current clinical practice. WIDER IMPLICATIONS OF THE FINDINGS Although IVM is considered to be a convenient, inexpensive and safe alternative to IVF for women with PCOS, our results indicated that one cycle of IVM without any stimulation was inferior to one cycle of standard IVF in terms of the cumulative live birth rate. The inferiority of IVM without ovarian stimulation could be mainly due to the limitations in the developmental potential of embryos. Further IVM development should be tested and validated in a freeze-only and blastocyst transfer setting. Further RCTs are needed to evaluate the effectiveness and safety of other IVM protocols or multiple cycles of IVM compared to IVF. STUDY FUNDING/COMPETING INTEREST(S) This study was supported by the National Key Research and Development Program of China (2016YFC1000201 and 2018YFC1002104) and the National Science Foundation of China (81730038). B.W.M. is supported by a NHMRC Investigator grant (GNT1176437). All other authors declare no competing interests. TRIAL REGISTRATION NUMBER Clinicaltrials.gov NCT03463772. TRIAL REGISTRATION DATE 29 January 2018. DATE OF FIRST PATIENT’S ENROLMENT 16 March 2018.

Despite several existing studies on the age at natural menopause (ANM) and its related factors, epidemiologic data on the associations between chronic diseases and ANM are scarce with conflicting and inconclusive results. The aim of this systematic review was to summarize the results of the studies investigating the association between chronic disease and ANM. PubMed, Scopus, and Web of Science were searched for retrieving and summarizing studies published up to October 2020 investigating the association between chronic medical conditions and ANM. All types of observational studies published in the English language were eligible to be included in the systematic review. Studies needed to report the effect of at least one chronic disease on ANM. Studies with other designs, studies with unreliable and incomplete results, and those that assessed none of the chronic diseases as outcomes of interest were excluded. Of the 6294 records retrieved by searching the databases, a total of 28 observational studies were included for this review. According to the Newcastle-Ottawa scale, nine studies were classified as high-quality, fifteen studies as moderate, and four as low-quality. Among the five studies investigating the association between polycystic ovary syndrome (PCOS) and ANM, three studies reported that PCOS was associated with a later ANM, whereas others found no such association. Eight studies showed that diabetes was associated with an earlier ANM, whereas eight other studies found no such association. While only one study showed a younger age at the onset of menopause in patients with a history of hypertension, five studies did not report such an effect. Only one study assessed the effect of dyslipidemia on ANM and showed no association between these variables. While three studies documented the effects of cardiovascular diseases (CVD) and heart disease on earlier ANM, one study found no association between these diseases and ANM. Most included studies showed the association of mood disorders with earlier ANM. There were no sufficient data for assessing the effects of thyroid, skin, and autoimmune diseases on ANM. Chronic diseases particularly cardio-metabolic disturbances, cardiovascular events, and psycho-emotional disorders are associated with earlier menopause, whereas other diseases such as PCOS may lead to later menopause. Accordingly, early diagnosis and managing chronic medical conditions in women can potentially prevent early or late menopause.

Different metabolic and hormonal disorders like type 2 diabetes mellitus (T2DM), obesity, and polycystic ovary syndrome (PCOS) have tangible socio-economic impact. Prevalence of these metabolic and hormonal disorders is steadily increasing among women. There are clinical evidences that these physiological conditions are related to the manifestation of different gynecological cancers and their poor prognosis. The relationship between metabolic and hormonal disorders with gynecological cancers is quite complex. The need for gene level association study is extremely important to find markers and predicting risk factors. In the current work, we have selected metabolic disorders like T2DM and obesity, hormonal disorder PCOS, and 4 different gynecological cancers like endometrial, uterine, cervical, and triple negative breast cancer (TNBC). The gene list was downloaded from DisGeNET database (v 6.0). The protein interaction network was constructed using HIPPIE (v 2.2) and shared proteins were identified. Molecular comorbidity index and Jaccard coefficient (degree of similarity) between the diseases were determined. Pathway enrichment analysis was done using ReactomePA and significant modules (clusters in a network) of the constructed network was analyzed by MCODE plugin of Cytoscape. The comorbid conditions like PCOS-obesity found to increase the risk factor of ovarian and triple negative breast cancers whereas PCOS alone has highest contribution to the endometrial cancer. Different gynecological cancers were found to be differentially related to the metabolic/hormonal disorders and comorbid condition.

Objectives This study aimed to determine the safety and efficacy of canagliflozin in comparison to metformin in polycystic ovary syndrome (PCOS) patients with insulin resistance (IR). Methods A single center, prospective, randomized open-label (ratio 1:1) non-inferiority trial was conducted at the Department of Endocrinology, Shanghai Tenth People's Hospital, between July 2019 and April 2021. Women aged 18-45 years with PCOS and IR were enrolled and randomly assigned to either 100 mg (n = 33) canagliflozin daily or 1500-2000 mg metformin daily (n = 35) for 12 weeks. The primary outcome was changes in homeostatic model assessment (HOMA)-IR after 12 weeks of treatment. The secondary outcomes included changes in anthropometric measurements, menstrual frequency, sex hormone levels, metabolic parameters, and body fat distribution. Results For lowering of HOMA-IR after 12 weeks of treatment, canagliflozin was found to be non-inferior to metformin (least-squares mean difference -0.81% [95% CI: -2.13 to 0.51]). Both canagliflozin and metformin could significantly improve menstrual pattern, reduce body weight and total fat mass, and decrease triglyceride levels. Compared with metformin, canagliflozin had significant advantages in reducing uric acid and dehydroepiandrosterone sulfate levels. Pruritus vulvae (9.09%) and gastrointestinal reaction (55.55%) were the main adverse events in the metformin group and canagliflozin group, respectively. Conclusion Our study demonstrates that canagliflozin was not inferior to metformin in PCOS patients with IR, which suggests that sodium-glucose co-transporter 2 inhibitors should be considered as effective drugs in the treatment of PCOS patients with IR. This article is protected by copyright. All rights reserved.

BACKGROUND Irisin is an adipo-myokine with potential implications in metabolic disorders such as polycystic ovary syndrome (PCOS). Despite of a strong evidence showing increased irisin level in PCOS, there is no conclusive evidence on the effect of metformin intervention on circulatory irisin in PCOS. AIM The aim of this meta-analysis was to compare the circulatory (serum/plasma) irisin levels before and after metformin intervention in subjects with PCOS. METHODS Relevant studies were retrieved by online database and manual searching. The standardized mean differences (SMDs) with 95% confidence intervals (CIs) were obtained by a random-effects meta-analysis. A one-study leave-out sensitivity analysis was conducted to validate the overall obtained results. RESULTS A total of five observations were included in this meta-analysis. The results based on random effects meta-analysis indicated that irisin levels were significantly decreased after metformin intervention as compared to the baseline pretreatment levels in PCOS (SMD: -1.00, 95% CI: -1.60 to -0.41, Z: 3.29, p = .001). The sensitivity analysis leaving-out a particular observation at a time and repeating the meta-analysis validated the robustness of the overall finding suggesting the significant effect of metformin treatment on irisin levels in PCOS. CONCLUSION Circulating irisin levels were significantly decreased upon metformin intervention in PCOS patients. The higher pretreatment irisin levels in PCOS may recede once the altered metabolic state is restored upon metformin intervention. Well-designed randomized trials with large sample sizes are warranted to further substantiate the reported evidence reported and to establish the possible mechanisms.

STUDY QUESTION Do extrinsic factors including lifestyle, psychosocial factors and healthcare professional engagement independently contribute to weight gain in women with and without polycystic ovary syndrome (PCOS)? SUMMARY ANSWER Women with PCOS had a higher rate of weight gain than women without PCOS which was most marked in those with unhealthy lifestyles. WHAT IS KNOWN ALREADY Women with PCOS have a higher prevalence of overweight/obesity and greater weight gain than women without PCOS. The association of lifestyle factors with weight change in PCOS is not known. STUDY DESIGN, SIZE, DURATION The study was a population-based observational study with data collected from seven surveys over 19 years (N = 14 127; Survey 1) involving women with and without PCOS. PARTICIPANTS/MATERIALS, SETTING, METHODS We used data from the 1973–1978 birth cohort of the Australian Longitudinal Study on Women’s Health. MAIN RESULTS AND THE ROLE OF CHANCE Women with PCOS gained more weight annually (0.26 kg/year; 95% CI 0.12, 0.39; P < 0.0001) and over 19 years (4.62 kg; 95% CI 3.04, 6.21; P < 0.0001) than women without PCOS (adjusted analyses). For all women, there were positive associations between weight gain and energy intake, sitting time and stress; inverse associations with fibre intake and physical activity (PA); and no associations with diet quality, glycaemic index, healthcare utilization, depression or anxiety. There were interactions between lifestyle factors (energy intake P = 0.006, glycaemic index P = 0.025, sitting time P = 0.041 and PA P = 0.021), PCOS status and time such that weight gain varied between women with and without PCOS according to these factors. LIMITATIONS, REASONS FOR CAUTION The limitations of this study include the use of self-reported measures such as diet, PA, sitting time, psychological factors and health care utilization. WIDER IMPLICATIONS OF THE FINDINGS While women with PCOS are more prone to weight gain, lifestyle factors have a more profound impact on weight gain in women with PCOS than without PCOS. These study findings have implications for understanding the mechanisms of weight gain in women with PCOS. They also highlight the importance of early lifestyle intervention as soon as PCOS is diagnosed to address modifiable extrinsic factors and prevent excess weight gain and worsening of the clinical features of PCOS. STUDY FUNDING/COMPETING INTEREST(S) M.A.A. is funded by the Monash International Tuition Scholarship and Monash Graduate Scholarship and L.J.M. is funded by a National Heart Foundation Future Leader Fellowship. The authors declared no conflict of interest. TRIAL REGISTRATION NUMBER N/A.

Context First-degree relatives of women with polycystic ovary syndrome (PCOS) present hormonal and metabolic alterations compared to girls unrelated to PCOS. It is unknown whether glucose intolerance in the PCOS proband confers a more severe metabolic predisposition on their first-degree relatives. Objective To determine whether glucose tolerance status in women with PCOS is associated with worsened glucose metabolism and sex hormone levels in their peripubertal daughters or sisters. Design Cross-sectional study. Setting Seven academic centers in North America, South America, and Europe. Patients Sixty-four pairs of women with PCOS and their daughters or younger sisters aged between 8 and 14 years were recruited. Twenty-five mothers or older sisters with PCOS were glucose intolerant (GI) and 39 were normal glucose tolerant (NGT). Main Outcome Measures Beta-cell function estimated by the insulin secretion-sensitivity index-2 (ISSI-2) during an oral glucose tolerance test and by the disposition index during a frequently sampled IV glucose tolerance test. Free testosterone and 17-hydroxyprogesterone (17-OHP) levels. Results Being related to a GI PCOS proband was associated with a lower ISSI-2 (P-value = 0.032) after adjusting for ethnicity, body mass index z-score, and pubertal stage. They also had higher free testosterone (P-value = 0.011) and 17-OHP levels compared to girls with an NGT proband, the latter becoming significant after adjusting for confounders (P-value = 0.040). Conclusions Compared to first-degree female relatives of women with PCOS and NGT, first-degree relatives of women with PCOS and GI display lower beta-cell function and hyperandrogenemia, putting them at higher risk of GI and PCOS development.

What is known and objective Although several clinical trials have compared the clinical efficacy of clomiphene citrate (CC) combined with metformin (MET) in the treatment of women with polycystic ovary syndrome (PCOS), the results are controversial. Therefore, this study was designed to conduct a pooled analysis to evaluate the efficacy of CC combined with MET versus CC in these patients. Methods Computerized searches of the PubMed, Web of Science, Embase and Cochrane Library databases were conducted to identify eligible randomized controlled trials (RCTs) from the data obtained up to June 2021. The Cochrane Collaboration risk of bias tool was used to assess the risk of bias in individual RCTs, and RevMan 5.4 was used for data statistical analysis. Results and discussion A total of 13 RCTs were included in the meta-analysis. These studies involved 1,353 patients, 707 of these were in the combination group and 646 in the monotherapy group. The results indicated a higher clinical pregnancy rate (risk ratio [RR] 1.28, 95% confidence interval [CI] 1.06-1.54, p = 0.01) in the combined group compared to the monotherapy group. However, no significant differences were observed in the ovulation rate (RR 1.13, 95% CI 0.98-1.30, p = 0.10), live birth rate (RR 1.13, 95% CI 0.89-1.42, p = 0.32), multiple pregnancy rate (RR 0.58, 95% CI 0.19-1.73, p = 0.33) and abortion rate (RR 1.26, 95% CI 0.86-1.84, p = 0.23) between the two groups. What is new and conclusion CC combined with MET has an advantage in improving the clinical pregnancy rate compared to CC alone; however, there is no significant difference in the rate of ovulation. For better management of PCOS, a high-quality RCT is needed to demonstrate the safety of the combination.

STUDY QUESTION Can serum anti-Müllerian hormone (AMH) replace polycystic ovary morphology (PCOM) determined by ultrasound as a diagnostic component of polycystic ovary syndrome (PCOS)? SUMMARY ANSWER Despite good correlations between serum AMH and PCOM, the use of a high serum AMH as a proxy for PCOM resulted in the reclassification of PCOS in 5% of study participants, with the main effect being more women identified, although some women previously classified as having PCOS were no longer classified as such. WHAT IS KNOWN ALREADY AMH has been proposed as an alternative to PCOM as a diagnostic component of PCOS. Previous studies are limited by poorly defining PCOS, use of infertile women as comparators, measurement of hormones by immunoassay that lack precision in the female range, low-resolution ovarian ultrasound and inconsistent handling and storage of serum samples. STUDY DESIGN, SIZE, DURATION This is an Australian cross-sectional study of 163 non-healthcare-seeking women. PARTICIPANTS/MATERIALS, SETTING, METHODS Serum AMH was measured by both the Ansh picoAMH assay and the Beckman Coulter Access 2 (BA2) assay, in parallel with androgens measured by liquid chromatography–tandem mass spectrometry, in blood samples of women, not pregnant, breast feeding or using systemic steroids, who also underwent high-resolution ovarian ultrasound. PCOS was determined by the Rotterdam criteria with PCOM defined by the Androgen Excess-PCOS Taskforce recommendation of ≥25 follicles in at least one ovary. Cut-off serum concentrations that best identified women as having PCOM were identified by receiver operator characteristic (ROC) curves. MAIN RESULTS AND THE ROLE OF CHANCE A total of 163 women, mean (SD) age 32.5 (5.5) years, who provided a blood sample and had both ovaries visualized on ultrasound were included in the analysis. Women with isolated PCOM had higher median (range) Ansh AMH and BA2 AMH concentrations than those with no PCOS characteristics [56.9 pmol/l (34.6, 104.2) versus 18.7 (3.2, 50.9), P = 0.002 and 38.5 pmol/l (22.2, 100.2) versus 16.7 (3.5, 38.9), P = 0.002, respectively]. An AMH ≥ 44.0 pmol/l, suggested by the ROC curve, identified 80.6% of women with PCOM, falsely identified 15.2% of women without PCOM as having PCOS and had a positive predictive value of 55.6%. The negative predictive value was 94.9%. An AMH BA2 assay cut-off of ≥33.2 pmol/l provided a sensitivity of 80.6%, a specificity of 79.5% and a positive predictive value for PCOM of 48.1%. The negative predictive value was 94.6% for PCOM. When serum AMH was used in the place of PCOM as a diagnostic criterion for PCOS, the Ansh assay resulted in an additional seven women classified as having PCOS and no longer classified one woman as having PCOS. For the BA2 assay, eight additional and two fewer women were classified as having PCOS. Overall, both assays resulted in six more women being classified as having PCOS. LIMITATIONS, REASONS FOR CAUTION Women with functional hypogonadotrophic hypogonadism were not excluded and may have been misclassified as having an oligo-amenorrhoea-PCOM phenotype. As study participants were predominantly Caucasian/White, our findings cannot be generalized to women of other ethnicities. WIDER IMPLICATIONS OF THE FINDINGS Although serum AMH reflects the number of developing ovarian follicles, the absolute values vary between assays and specific reference ranges for individual assays are required. Irrespective of the assay used, replacing PCOM with serum AMH to diagnose PCOS in a community-based sample altered the number of women classified as having or not having PCOS. Consequently, although overall the risk of women being identified as having PCOS would be increased, some women would no longer be classified as having this condition. STUDY FUNDING/COMPETING INTEREST(S) The study was supported by the Norman Beischer Research Foundation and the Grollo-Ruzzene Foundation. S.R.D. is an NHMRC Senior Principal Research Fellow (Grant No. 1135843). S.R.D. reports unrelated support that includes grants from the NHMRC Australia, personal fees for educational activities from Besins Healthcare, Abbott Chile, BioFemme and Pfizer Australia, personal Advisory Board/consultancy fees from Theramex, Abbott Laboratories, Astellas, Mayne Pharmaceuticals, Roche Diagnostics, Lawley Pharmaceuticals and Que Oncology and has received institutional grant funding from Que Oncology and Ovoca research. The other authors declare no conflicts of interest. TRIAL REGISTRATION NUMBER N/A.

Background:. Obesity and insulin resistance (IR) are common features of polycystic ovary syndrome (PCOS). Metformin (MET) increases insulin sensitivity, but it is associated with unsatisfactory weight loss. The glucagon-like peptide-1 receptor agonist exenatide has been shown to reduce weight and IR in patients with diabetes. This study aimed to explore the therapeutic effects of exenatide once-weekly (QW) combined with MET on body weight, as well as metabolic and endocrinological parameters in overweight/obese women with PCOS. Methods:. Fifty overweight/obese women with PCOS diagnosed via the Rotterdam criteria were randomized to one of two treatment groups: MET (500 mg three times a day [TID]) or combination treatment (COM) (MET 500 mg TID, exenatide 2 mg QW) for 12 weeks. The primary outcomes were anthropometric changes associated with obesity, and the secondary outcomes included changes in reproductive hormone levels, glucose and lipid metabolism, and C-reactive protein. Results:. Forty (80%) patients completed the study. COM therapy was superior to MET monotherapy in reducing weight (P = 0.045), body mass index (BMI) (P = 0.041), and waist circumference (P = 0.023). Patients in the COM group on an average lost 3.8 ± 2.4 kg compared with 2.1 ± 3.0 kg in the MET group. In the COM group, BMI and waist circumference decreased by 1.4 ± 0.87 kg/m2 and 4.63 ± 4.42 cm compared with 0.77 ± 1.17 kg/m2 and 1.72 ± 3.07 cm in the MET group, respectively. Moreover, levels of fasting glucose, oral glucose tolerance test (OGTT) 2-h glucose, and OGTT 2-h insulin were significantly lower with COM therapy than with MET (P

Polycystic ovary syndrome (PCOS) is a common endocrine disorder among reproductive-age women. Insulin resistance and dyslipidemia are linked to PCOS. l-Carnitine supplementation as a management strategy for women with PCOS has been proposed. The effect of l-carnitine supplementation on insulin resistance, sex hormone-binding globulin (SHBG) and lipid profile in overweight/obese women with PCOS was investigated. This randomized, double-blind, controlled clinical trial, was conducted on 62overweight/obese women with PCOS. Participants were randomly assigned into two groups to receive 1000 mg/day l-carnitine or placebo (1000 mg starch) for 12 weeks. l-Carnitine supplementation compared to the placebo showed a significant improvement in insulin [− 0.7 (− 7.3 to 4.0) vs. 0.7 (− 3.0 to 5.2); P = 0.001], homeostatic model assessment for insulin resistance [− 0.4 (− 1.7 to 1.1) vs. 0.0 (− 0.7 to 1.3); P = 0.002], quantitative insulin sensitivity check index (+ 0.01 ± 0.02 vs. − 0.01 ± 0.01; P = 0.02) and a non-significant change toward improvement in SHBG (+ 11.5 ± 40.2 vs. − 3.2 ± 40.2; P = 0.2). However, there was no significant differences between the two groups in serum levels of fasting plasma glucose, total cholesterol, triglyceride, low density lipoprotein-cholesterol and high density lipoprotein cholesterol (P > 0.05). 12-week l-carnitine supplementation in overweight or obese women with PCOS ameliorate insulin resistance, but has no effect on SHBG and lipid profile. Studies with higher dosages and duration of l-carnitine intake are required. The trial was registered on 30 December 2019 at Iranian Registry of Clinical Trials IRCT20191016045131N1. Registered on 30th December 2019 at Iranian Registry of Clinical Trials (IRCT20191016045131N1).

Utilizing corifollitropin alfa in GnRH antagonist (GnRHant) protocol in conjunction with GnRH agonist trigger/freeze-all strategy (corifollitropin alfa/GnRHant protocol) was reported to have satisfactory outcomes in women with polycystic ovary syndrome (PCOS). Although lessening in gonadotropin injections, GnRHant were still needed. In addition to using corifollitropin alfa, GnRHant was replaced with an oral progestin as in progestin primed ovarian stimulation (PPOS) to further reduce the injection burden in this study. We try to investigate whether this regimen (corifollitropin alfa/PPOS protocol) could effectively reduce GnRHant injections and prevent premature LH surge in PCOS patients undergoing IVF/ICSI cycles. This is a retrospective cohort study recruiting 333 women with PCOS, with body weight between 50 and 70 kg, undergoing first IVF/ICSI cycle between August 2015 and July 2018. We used corifollitropin alfa/GnRHant protocol prior to Jan 2017 (n = 160), then changed to corifollitropin alfa/PPOS protocol (n = 173). All patients received corifollitropin alfa 100 μg on menstruation day 2/3 (S1). Additional rFSH was administered daily from S8. In corifollitropin alfa/GnRHant group, cetrorelix 0.25 mg/day was administered from S5 till the trigger day. In corifollitropin alfa/PPOS group, dydrogesterone 20 mg/day was given from S1 till the trigger day. GnRH agonist was used to trigger maturation of oocyte. All good quality day 5/6 embryos were frozen, and frozen-thawed embryo transfer (FET) was performed on subsequent cycle. A comparison of clinical outcomes was made between the two protocols. The primary endpoint was the incidence of premature LH surge and none of the patients occurred. Dydrogesterone successfully replace GnRHant to block LH surge while an average of 6.8 days of GnRHant injections were needed in the corifollitropin alfa/GnRHant group. No patients suffered from ovarian hyperstimulation syndrome (OHSS). The other clinical outcomes including additional duration/dose of daily gonadotropin administration, number of oocytes retrieved, and fertilization rate were similar between the two groups. The implantation rate, clinical pregnancy rate, and live birth rate in the first FET cycle were also similar between the two groups. In women with PCOS undergoing IVF/ICSI treatment, corifollitropin alfa/PPOS protocol could minimize the injections burden with comparable outcomes to corifollitropin alfa/GnRHant protocol.

Polycystic ovary syndrome (PCOS) is a multifactorial reproductive and endocrine disease, believed to be caused by aberrant steroid biosynthesis pathways involving cytochrome P450, 17α-hydroxylase (CYP17A1). This meta-analysis aimed to evaluate the association between CYP17A1 polymorphism rs743572 and PCOS risk. Studies on the CYP17A1 gene were retrieved by searching PubMed, Embase and Web of Science and statistical analyses were performed by STATA software. Fifteen eligible studies were included, dated from January 1994 to 19 November 2020, involving 2277 patients with PCOS and 1913 control individuals. Overall, the results showed that the rs743572 T>C mutation was most likely to be associated with PCOS risk under the recessive model, which was further confirmed by heterogeneity analysis and publication bias detection (CC versus CT + TT, odds ratio [OR] 1.24, 95% confidence interval [CI] 1.02–1.50, P = 0.028, I² = 35.9%). Moreover, subgroup analysis by ethnicity demonstrated that Caucasian but not Asian women carrying the CC genotype of rs743572 had an elevated risk of PCOS (CC versus CT + TT, OR 1.45, 95% CI 1.03–2.06, P = 0.035, I² = 15.10%, six studies). In conclusion, rs743572 is highly likely to be a risk factor for PCOS, and the mutant genotype CC may increase susceptibility to PCOS in Caucasians rather than Asians.

Mengxiong Li,1,&ast; Zhi Zeng,2,&ast; Aiqing Zhang,3 Qingjian Ye,4 Shujun Su,4 Tingting Xia5 1Department of Obstetrics and Gynecology, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong, 518107, People’s Republic of China; 2The Department of Reproductive Medicine Center, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, 510000, People’s Republic of China; 3Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, 510630, People’s Republic of China; 4Department of Gynecology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, 510630, People’s Republic of China; 5Center for Reproductive Medicine, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, 510630, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Tingting Xia Tel +86-020-85256032Email xiatting@mail.sysu.edu.cnObjective: Dysfunction of cumulus granulosa cells has been suggested as a contributor to abnormal folliculogenesis and the development of polycystic ovary syndrome (PCOS), but the underlying molecular mechanisms remain unclear. Recent studies indicate that circular RNAs (circRNAs) exert important roles for diseases. We aimed to screen crucial circRNAs of PCOS patients and predict their functions.Methods: The high-throughput datasets of circRNAs (GSE145296), microRNAs (miRNAs; GSE72274) and messenger RNAs (mRNAs; GSE155489) in cumulus cells of PCOS patients and controls were collected from the Gene Expression Omnibus database. Differentially expressed circRNAs (DECs), miRNAs (DEMs) and protein-coding genes (DEGs) were identified by the limma method. The weighted correlation network analysis (WGCNA) was conducted using the DECs to mine PCOS-associated modules. Hub DECs in modules were defined as both of |gene significance| and |module membership| > 0.8. The downstream effectors of hub DECs were predicted by constructing DEC-DEM-DEG ceRNA and DEC-RNA binding protein (RBP) networks. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed to explore the functions of circRNAs.Results: A total of 3614 DECs, 3544 DEGs and 1469 DEMs were identified between PCOS and controls. WGCNA analysis yielded five PCOS-related modules, of which 190 DECs were hub circRNAs. Seventeen hub DECs, nine DEMs, and 315 DEGs were identified to construct the ceRNA network, while 56 hub DECs and two DEGs (MBNL2, RBPMS) constituted the circRNA-RBP network. Five hub DECs (hsa_circ_0063309, hsa_circ_0054275, hsa_circ_0056196, hsa_circ_0018108 and hsa_circ_0070987) were overlapped between ceRNA and DEC-MBNL2 regulatory networks and thus they may be pivotal for PCOS. Furthermore, hsa_circ_0099109 could interact with the RBP gene RBPMS. Function analyses showed these circRNAs were inflammation-, apoptosis- or steroidogenesis-related.Conclusion: Aberrant expression of six circRNAs that function as RBP regulators or miRNA sponges may be possible mechanisms underlying the pathogenesis of PCOS by affecting apoptosis and steroidogenesis in cumulus cells.Keywords: circular RNAs, competitive endogenous RNAs, polycystic ovary syndrome, RNA-binding proteins, weighted gene co-expression network analysis

Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women of reproductive age. Metformin is introduced for treatment of women with PCOS, and the beneficial effects of exercise in women with PCOS are found for a range of outcomes. Our aim is to compare the effects of metformin plus exercise with exercise intervention in PCOS on clinical, anthropometric, metabolic, and psychological parameters. MEDLINE, EMBASE, Web of Science and China National Knowledge Infrastructure were searched for studies. Nine studies were considered eligible for inclusion. The meta-analysis reveals that metformin offers additive benefits to exercise, leading to modest improvements in menstrual cycles, hyperandrogenism, and abdominal fat.

OBJECTIVE To determine the changes of circulating periostin levels in polycystic ovary syndrome (PCOS) and its relationship with metabolic disorders. STUDY DESIGN Cross-sectional study. PLACE AND DURATION OF STUDY Konya Research and Training Hospital, Turkey between September 2018 and April 2020. METHODOLOGY Patients with PCOS were compared with healthy individuals as control. The demographics, laboratory findings, anthropometric measurements, the levels of serum periostin and carotid intima media thickness (CIMT) were evaluated and compared. RESULTS There was no significant difference between patients with PCOS (n = 53) and controls (n = 35), according to demographic and laboratory findings and anthropometric measurements. The CIMT in patients with PCOS and control groups were measured as 0.5 ± 0.06 mm and 0.43 ± 0.1 mm, respectively (p

Objective: The aim of this study was to determine the serum adiponectin and interleukin-36 alpha (IL-36α) levels in polycystic ovary syndrome (PCOS), and their relationship with obesity. Materials and methods: This observatory study included 80 PCOS patients and 58 controls. The clinical, biochemical, and hormonal parameters, and serum adiponectin and IL-36α levels of the patients were evaluated. Results: The serum IL-36α levels of the PCOS patients were significantly lower when compared to the control group, despite a similar mean body mass index (BMI) (P = 0.000). The adiponectin levels were significantly lower in the obese PCOS group when compared to the obese control group (P = 0.03). The plasma IL-36α level was positively correlated with adiponectin level, but negatively correlated with the serum LH level (P = 0.000 and P = 0.004, respectively). Using receiver operating characteristic analysis, the cut-off value of IL-36α was calculated as 0.815 for PCOS. In the multiple binary logistic regression analysis, IL-36α (OR [95% CI] 0.432 [0.303, 0.616], P

Background Insulin resistance and hormonal imbalances are key features in the pathophysiology of polycystic ovarian syndrome (PCOS). We have previously shown that Ficus deltoidea var. deltoidea Jack (Moraceae) can improve insulin sensitivity and hormonal profile in PCOS female rats. However, biological characteristics underpinning the therapeutic effects of F. deltoidea for treating PCOS remain to be clarified. This study aims to investigate the biochemical, hormonal, and histomorphometric changes in letrozole (LTZ)-induced PCOS female rats following treatment with F. deltoidea. Methods PCOS was induced in rats except for normal control by administering LTZ at 1 mg/kg/day for 21 days. Methanolic extract of F. deltoidea leaf was then orally administered to the PCOS rats at the dose of 250, 500, or 1000 mg/kg/day, respectively for 15 consecutive days. Lipid profile was measured enzymatically in serum. The circulating concentrations of reproductive hormone and antioxidant enzymes were determined by ELISA assays. Ovarian and uterus histomorphometric changes were further observed by hematoxylin and eosin (H&E) staining. Results The results showed that treatment with F. deltoidea at the dose of 500 and 1000 mg/kg/day reduced insulin resistance, obesity indices, total cholesterol, triglycerides, low-density lipoprotein cholesterol (LDL), malondialdehyde (MDA), testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) to near-normal levels in PCOS rats. The levels of high-density lipoprotein cholesterol (HDL), estrogen, and superoxide dismutase (SOD) are also similar to those observed in normal control rats. Histomorphometric measurements confirmed that F. deltoidea increased the corpus luteum number and the endometrial thickness. Conclusions F. deltoidea can reverse PCOS symptoms in female rats by improving insulin sensitivity, antioxidant activities, hormonal imbalance, and histological changes. These findings suggest the potential use of F. deltoidea as an adjuvant agent in the treatment program of PCOS.

Inflammation and dyslipidemia are often present in polycystic ovary syndrome (PCOS). We determined the effect of saturated fat ingestion on circulating heat shock protein-70 (HSP-70) and mononuclear cell (MNC) toll-like receptor-2 (TLR2) gene expression, activator protein-1 (AP-1) activation, and matrix matalloproteinase-2 (MMP-2) protein in women with PCOS. Twenty reproductive-age women with PCOS (10 lean, 10 with obesity) and 20 ovulatory controls (10 lean, 10 with obesity) participated in the study. HSP-70 was measured in serum and TLR2 mRNA and protein, AP-1 activation, and MMP-2 protein were quantified in MNC from blood drawn while fasting and 2, 3, and 5 h after saturated fat ingestion. Insulin sensitivity was derived from an oral glucose tolerance test (IS(OGTT)). Androgen secretion was assessed from blood drawn while fasting and 24, 48, and 72 h after human chorionic gonadotropin (HCG) administration. In response to saturated fat ingestion, serum HSP-70, TLR2 gene expression, activated AP-1, and MMP-2 protein were greater in lean women with PCOS compared with lean controls and in women with PCOS and obesity compared with controls with obesity. Both PCOS groups exhibited lower IS(OGTT) and greater HCG-stimulated androgen secretion compared with control subjects of their respective weight classes. Lipid-stimulated proatherogenic inflammation marker responses were negatively correlated with IS(OGTT) and positively correlated with abdominal adiposity and HCG-stimulated androgen secretion. In PCOS, saturated fat ingestion stimulates proatherogenic inflammation independent of obesity. This effect is greater when PCOS is combined with obesity compared with obesity alone. Abdominal adiposity and hyperandrogenism may perpetuate proatherogenic inflammation. NEW & NOTEWORTHY This paper demonstrates that in polycystic ovary syndrome (PCOS), ingestion of saturated fat triggers a molecular pathway of inflammation known to drive atherogenesis. This effect is independent of obesity as it occurs in lean women with PCOS and not in lean ovulatory control subjects. Furthermore, the combined effects of PCOS and obesity are greater compared with obesity alone.